Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types. Here, we combine cell-type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels.
A strocytes, the most abundant glial cells in the brain, are found to associate closely with neuronal synapses (1, 2). Although astrocytes lack excitability in terms of action potentials, they express various neurotransmitter receptors and ion channels and can create Ca 2ϩ waves in response to various stimuli, including neuronal activity. Furthermore, astrocytes can secrete many factors that modulate neuronal activity (3-5). Recent studies have shown that astrocytes play important roles in neurogenesis (6), synaptogenesis (7,8), and synaptic modulation (3-5, 9-11). There is evidence that astrocytes may also contribute to high-level brain functions such as motivation, learning, and behavior (12). Given the potential role of glial factors in neuronal functions, it is of interest to know whether and how astrocytes may contribute to the induction of long-term potentiation (LTP), the most extensively studied form of synaptic plasticity that may serve as a cellular mechanism underlying learning and memory (13,14). Deletion of glial fibrillary acidic protein (GFAP) or S-100B in the mouse (15, 16) resulted in an enhancement of LTP, but how these cytoplasmic proteins in glial cells affect synaptic plasticity remains unknown. Studies of LTP are usually carried out in slice preparations, in which glial cells are intimately associated with neurons and synapses. It is thus difficult to separate the role of glia in synaptogenesis from a direct modulatory role of glial factors in synaptic plasticity. To address this problem, we have established in the present study two types of hippocampal neuronal cultures: conventional mixed cultures, in which neurons were grown on a layer of astrocytes, and cultures in which the neurons were fed with glial conditioned medium (GCM) but grown without contacting astrocytes (see Materials and Methods). In the latter GCM cultures, apparently normal synaptogenesis occurs among hippocampal neurons. By using correlated stimulation of pre-and postsynaptic neurons to induce LTP (17), we were able to analyze directly the role of immediate astrocyte-derived factors in the induction of LTP. We found that LTP could be induced in mixed cultures, but not in GCM cultures, and that glia-derived D-serine plays a key role in LTP induction by its action on the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptors. Furthermore, we showed that in hippocampal slices, the induction of LTP at Schaffer collateral-CA1 pyramidal cell synapses also critically depends on the presence of intact glial cells and extracellular D-serine. Taken together, we have identified an astrocyte-derived factor that contributes to activity-induced long-term synaptic plasticity. Materials and MethodsCell Cultures. Primary cultures of astrocytes were prepared as described (18, 19) with some modifications. In brief, cortices were prepared from 1-d-old rat and were dissociated by trypsin, plated on polyD-lysine-coated glass coverslips, cultured with Eagle's MEM (GIBCO) containing 10% FBS, and maintained at 37°C in a 5% CO 2 incubato...
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